The active hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 (1.25(OH)2D3), has a central role in calcium and phosphate homeostasis, and the maintenance of bone. Apart from these calcitropic effects, 1,25-(OH)2D3 has been shown to play a role in controlling cell growth and differentiation in many target tissues. The effects of 1,25-(OH)2D3 are mediated by a specific receptor protein, the vitamin D receptor (VDR), a member of the nuclear receptor superfamily of transcriptional regulators which also includes steroid, thyroid and retinoid receptors as well as a growing number of orphan receptors. Upon binding hormone the VDR regulates gene expression by direct interaction with specific sequence elements in the promotor regions of hormone responsive target genes. This transactivation or repression involves multiple interactions with other protein cofactors, heterodimerisation partners and the transcription machinery.
Although a cDNA encoding the human VDR was cloned in 1988 (1), little has been documented characterising the gene structure and pattern of transcription since that time. The regulation of VDR abundance is one potentially important mechanism for modulating 1.25-(OH)2D3 responsiveness in target cells. It is also possible that VDR has a role in non-transcriptional pathways, perhaps via localization to a non-nuclear compartment and/or interaction with components of other signalling pathways. However, the question of how VDRs are targetted to different cell types and how they are regulated remains unresolved. There have been many reports in the literature describing translational or transcriptional control of VDR levels, both homologously and heterologously, mostly in non-human systems.
A recent study (2) showed that in the kidney, alternative splicing of human VDR transcripts transcribed from a GC rich promotor generates several transcripts which vary only in their 5′ UTRs. The present inventors have now identified further upstream exons of the VDR gene which generate 5′ variant transcripts, suggesting that the expression of the VDR gene is regulated by more than one promoter. A subset of these transcripts is expressed in a restricted tissue-specific pattern and further variant transcripts have the potential to encode an N-terminally variant protein. These results may have implications for understanding the actions of 1,25-(OH)2D3 in different tissues and cell types, and the possibility that N-terminally variant VDR proteins may be produced has implications for altered activities such as transactivation function or subcellular localisation of the receptor protein. Furthermore, these variants, by their level, tissue specificity, subcellular localisation and functional activity, may yield targets for pharmaceutical intervention. The variants may also be useful in screening potential analogs and/or antagonists of vitamin D compounds.